Ly6Chi monocyte recruitment is responsible for Th2 associated host-protective macrophage accumulation in liver inflammation due to schistosomiasis

Accumulation of M2 macrophages in the liver, within the context of a strong Th2 response, is a hallmark of infection with the parasitic helminth, Schistosoma mansoni, but the origin of these cells is unclear. To explore this, we examined the relatedness of macrophages to monocytes in this setting. Our data show that both monocyte-derived and resident macrophages are engaged in the response to infection. Infection caused CCR2-dependent increases in numbers of Ly6Chi monocytes in blood and liver and of CX3CR1+ macrophages in diseased liver. Ly6Chi monocytes recovered from liver had the potential to differentiate into macrophages when cultured with M-CSF. Using pulse chase BrdU labeling, we found that most hepatic macrophages in infected mice arose from monocytes. Consistent with this, deletion of monocytes led to the loss of a subpopulation of hepatic CD11chi macrophages that was present in infected but not naïve mice. This was accompanied by a reduction in the size of egg-associated granulomas and significantly exacerbated disease. In addition to the involvement of monocytes and monocyte-derived macrophages in hepatic inflammation due to infection, we observed increased incorporation of BrdU and expression of Ki67 and MHC II in resident macrophages, indicating that these cells are participating in the response. Expression of both M2 and M1 marker genes was increased in liver from infected vs. naive mice. The M2 fingerprint in the liver was not accounted for by a single cell type, but rather reflected expression of M2 genes by various cells including macrophages, neutrophils, eosinophils and monocytes. Our data point to monocyte recruitment as the dominant process for increasing macrophage cell numbers in the liver during schistosomiasis

Filarial Lymphedema Is Characterized by Antigen- Specific Th1 and Th17 Proinflammatory Responses and a Lack of Regulatory T Cells

Background: Lymphatic filariasis can be associated with development of serious pathology in the form of lymphedema, hydrocele, and elephantiasis in a subset of infected patients. Methods and Findings: To elucidate the role of CD4+ T cell subsets in the development of lymphatic pathology, we examined specific sets of cytokines in individuals with filarial lymphedema in response to parasite antigen (BmA) and compared them with responses from asymptomatic infected individuals. We also examined expression patterns of Toll-like receptors (TLR1–10) and Nod-like receptors (Nod1, Nod2, and NALP3) in response to BmA. BmA induced significantly higher production of Th1-type cytokines—IFN-c and TNF-a—in patients with lymphedema compared with asymptomatic individuals. Notably, expression of the Th17 family of cytokines—IL-17A, IL-17F, IL-21, and IL-23—was also significantly upregulated by BmA stimulation in lymphedema patients. In contrast, expression of Foxp3, GITR, TGFb, and CTLA-4, known to be expressed by regulatory T cells, was significantly impaired in patients with lymphedema. BmA also induced significantly higher expression of TLR2, 4, 7, and 9 as well Nod1 and 2 mRNA in patients with lymphedema compared with asymptomatic controls. Conclusion: Our findings implicate increased Th1/Th17 responses and decreased regulatory T cells as well as regulation of Toll- and Nod-like receptors in pathogenesis of filarial lymphedema

The Effect of High Glucocorticoid Administration and Food Restriction on Rodent Skeletal Muscle Mitochondrial Function and Protein Metabolism

Glucocorticoids levels are high in catabolic conditions but it is unclear how much of the catabolic effects are due to negative energy balance versus glucocorticoids and whether there are distinct effects on metabolism and functions of specific muscle proteins.We determined whether 14 days of high dose methylprednisolone (MPred, 4 mg/kg/d) Vs food restriction (FR, food intake matched to MPred) in rats had different effects on muscle mitochondrial function and protein fractional synthesis rates (FSR). Lower weight loss (15%) occurred in FR than in MPred (30%) rats, while a 15% increase occurred saline-treated Controls. The per cent muscle loss was significantly greater for MPred than FR. Mitochondrial protein FSR in MPred rats was lower in soleus (51 and 43%, respectively) and plantaris (25 and 55%) than in FR, while similar decline in protein FSR of the mixed, sarcoplasmic, and myosin heavy chain occurred. Mitochondrial enzymatic activity and ATP production were unchanged in soleus while in plantaris cytochrome c oxidase activity was lower in FR than Control, and ATP production rate with pyruvate + malate in MPred plantaris was 28% lower in MPred. Branched-chain amino acid catabolic enzyme activities were higher in both FR and MPred rats indicating enhanced amino acid oxidation capacity.MPred and FR had little impact on mitochondrial function but reduction in muscle protein synthesis occurred in MPred that could be explained on the basis of reduced food intake. A greater decline in proteolysis may explain lesser muscle loss in FR than in MPred rats

Lack of Evidence for Neonatal Misoprostol Neurodevelopmental Toxicity in C57BL6/J Mice

Misoprostol is a synthetic analogue of prostaglandin E1 that is administered to women at high doses to induce uterine contractions for early pregnancy termination and at low doses to aid in cervical priming during labor. Because of the known teratogenic effects of misoprostol when given during gestation and its effects on axonal growth in vitro, we examined misoprostol for its potential as a neurodevelopmental toxicant when administered to neonatal C57BL6/J mice. Mice were injected subcutaneously (s.c.) with 0.4, 4 or 40 µg/kg misoprostol on postnatal day 7, the approximate developmental stage in mice of human birth, after which neonatal somatic growth, and sensory and motor system development were assessed. These doses were selected to span the range of human exposure used to induce labor. In addition, adult mice underwent a battery of behavioral tests relevant to neurodevelopmental disorders such as autism including tests for anxiety, stereotyped behaviors, social communication and interactions, and learning and memory. No significant effects of exposure were found for any measure of development or behavioral endpoints. In conclusion, the results of the present study in C57BL/6J mice do not provide support for neurodevelopmental toxicity after misoprostol administration approximating human doses and timed to coincide with the developmental stage of human birth

Adherence to daily dietary and activity goals set within a Māori and Pacific weight loss competition.

Background: New Zealand Pacific and Māori populations measure disproportionately high on the international body mass index (BMI). Information is needed on what behavioural weight loss goals to recommend and how to attract and retain them in interventions. Our team weight loss competition trial for participants with a BMI ≥30 used cash prizes to incentivise completion of nine daily behaviour goals. This paper evaluates the theoretical merit of and adherence to these goals. Methods: A qualitative component evaluation methodology was used. Trial data on team activity, demographics and anthropometric outcome data were extracted to determine frequency of daily goal completion by teams throughout the competition and to describe participant characteristics. T-tests were used to compare completion rates of the challenges, challenge completion by day of week and between weekdays and weekends. To examine adherence to the daily challenge activity over 24 weeks the total amount of completed challenges adjusted for number of active teams was plotted by week. A Body Shape Index (ABSI) was used to determine individual anthropometric change from baseline to 8, 16 and 24 weeks. Program documents were analysed to identify barriers to adherence and retention of participants. Results: Of 19 teams (N = 130) who began only five teams performed daily goals across the whole 24 weeks. Adherence was highest during the first 8 weeks. No difference in performance between goals was found suggesting they were equally viable, though tasks worth less points were performed more frequently. Goal completion was higher on weekdays. The behaviour goals appeared to have theoretical merit in that more members of high performing teams experienced a positive change in their ABSI. Conclusions: Incentives offer a promising strategy for encouraging retention in weight loss interventions. This study suggests that participants in a competition will perform incentivised tasks. The findings however, are limited by missing data and high drop out of individuals and whole teams. Further research is needed on how to increase retention.New Zealand Ministry of Healt

Chest CT and hospital outcomes in patients with omicron compared with delta variant SARS-CoV-2 infection

Background The SARS-Cov-2 Omicron variant demonstrates rapid spread but with reduced disease severity. Studies evaluating the lung imaging findings of Omicron infection versus non-Omicron variants remain lacking. Purpose To compare Omicron and Delta variants of SARS-CoV-2 by their chest CT radiological pattern, biochemical parameters, clinical severity and hospital outcomes after adjusting for vaccination status. Materials and Methods Retrospective study of hospitalized adult patients rt-PCR positive for SARS-CoV-2 with CT pulmonary angiography performed within 7 days of admission between December 1, 2021 and January 14, 2022. Blinded radiological analysis with multiple readers including RSNA CT classification, chest CT severity score (CT-SS, range 0 least severe to 25 most severe) and CT imaging features including bronchial wall thickening. Results 106 patients (Delta n=66, Omicron n=40) were evaluated (mean age, 58 years ± 18, 58 men). In the Omicron group, 37% (15/40) of CT pulmonary angiograms were categorized as normal compared with 15% (10/66) in the Delta group (p=.016). Using a generalized linear model to control for confounding variables, including vaccination status, Omicron variant infection was associated with a CT-SS that was lower by 7.2 points compared to infection with Delta variant (β=-7.2, 95%CI: -9.9, -4.5; p <.001). Bronchial wall thickening was more common with Omicron than with the Delta variant (odds ratio [OR] 2.4, 95%CI: 1.01, 5.92, p=.04). Vaccination with a booster shot was associated with a protective effect on chest infection compared with the unvaccinated (CT-SS median 5 (IQR 0-11), CT-SS median 11 (IQR 7.5-14), respectively; p = .03). The Delta variant was associated with a higher odds ratio of severe disease (OR 4.6, 95%CI: 1.2, 26, p=.01) and critical care admission (OR 7.0, 95%CI: 1.5, 66, p=.004) than the Omicron variant. Conclusion The SARS-COV-2 Omicron variant was associated with fewer and less severe changes on chest CT compared with the Delta variant. Patients with Omicron had greater frequency of bronchial wall thickening but lower clinical severity and improved hospital outcomes than those with Delta